ROLE OF T AND B CELLS IN MOUSE MAMMARY TUMOR VIRUS INFECTION

小鼠乳腺肿瘤病毒(MMTV)是第一个被证明在哺乳动物中致癌的病毒，并通过牛奶传播。长期以来，MMTV一直被研究为通过肠道相关淋巴组织或GalT感染的病毒的原型。MMTV含有一种名为超抗原(SAG)的病毒蛋白，使其能够感染淋巴样细胞，首先在肠道，然后是全身。我们认为，这使得MMTV可以通过感染的淋巴细胞从肠道传播到乳腺。该项目的目标之一是明确确定哪种类型的淋巴细胞对于向乳腺细胞传递MMTV是重要的，以及它们如何完成这一转移。将在体内研究受感染的淋巴细胞向乳腺的运输，并将使用抗体阻断技术和扰乱淋巴细胞向粘膜组织归巢的β-7-整合素/L-选择素基因敲除小鼠来检验干扰这种运输对病毒向该组织转移的影响。我们还将使用基因标记的病毒来观察被感染的特定淋巴细胞亚群，并确定病毒如何在不同细胞之间转移。除了MMTV在感染的早期阶段与淋巴样细胞相互作用外，人们认为这种病毒还会在后期颠覆免疫系统，这最终会影响其导致乳腺肿瘤的能力。因此，这项建议的另一个目的是确定MMTV是否诱导免疫耐受，以及SAG介导的T细胞删除是否在这一过程中发挥作用。由于小鼠是目前最好的基因可操纵性和免疫学特征良好的物种，我们对MMTV如何利用和颠覆免疫系统的研究将进一步加深我们对细胞类型、感染部位和宿主对逆转录病毒感染反应之间关系的理解。

Mouse mammary tumor virus (MMTV) was the first virus shown to cause cancer in mammals and is transmitted through milk. MMTV has long been studied as a prototype for viruses that are acquired through the gut- associated lymphoid tissue or GALT. MMTV contains a viral protein, called the superantigen (Sag), that enables it to infect lymphoid cells, first in the gut and then systematically. We believe that this allows MMTV to spread from the gut to the mammary gland via infected lymphocytes. One of the goals of this project is to determine specifically which type of lymphocytes are important for delivery MMTV to the mammary cell and how they accomplish this transfer. Trafficking of infected lymphocytes to the mammary gland will be studied in vivo and the effects of disrupting this trafficking on virus transfer to this tissue will be examined, using antibody blocking techniques and beta7-integrin/L-selectin knockout mice that have disrupted homing of lymphocytes to mucosal tissue. We will also use genetically-marked viruses to look at the specific lymphocyte subsets that are infected and to determine how virus transfer between different cells occur. In addition to MMTV's interaction with lymphoid cells at early stages of infection, be believe that this virus also subverts the immune system at later stages and this ultimately affects its ability to cause mammary tumors. Thus, another aim of this proposal is to determine whether MMTV induces immune tolerance and whether Sag- mediated deletion of T cells plays a role in this process. Because mice are currently the best genetically-manipulatable and immunologically well- characterized species available, our studies on how MMTV utilizes and subverts the immune system will further our understanding of the relationship between the cell type, site of infection and host response to retroviral infection.